Liu Mi, Zhu Yangyang, Sun Ying, Wen Zhaoying, Huang Songming, Ding Guixia, Zhang Aihua, Jia Zhanjun, Zhang Yue
Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, China.
Department of Cardiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
Oncotarget. 2017 Dec 7;9(1):394-403. doi: 10.18632/oncotarget.23037. eCollection 2018 Jan 2.
Ureteral obstruction is associated with reduced expressions of renal sodium transporters, which contributes to impaired urinary concentrating capacity. In this study, we employed a synthetic mitochondrial superoxide dismutase 2 (SOD2) mimic MnTBAP to investigate the role of mitochondrial oxidative stress in modulating the sodium transporters in obstructive kidney disease. Following unilateral ureteral obstruction (UUO) for 7 days, a global reduction of sodium transporters including NHE3, NCC, NKCC2, and ENaCα was observed as determined by qRT-PCR, Western Blotting or immunohistochemistry. Among these sodium transporters, the downregulation of NHE3, NCC, and NKCC2 was partially reversed by MnTBAP treatment. In contrast, the reduction of ENaCα was not affected by MnTBAP. The β and γ subunits of ENaC were not significantly altered by ureteral obstruction or MnTBAP therapy. To further confirm the anti-oxidant effect of MnTBAP, we examined the levels of TBARs in the urine collected from the obstructed ureters of UUO mice and bladder of sham mice. As expected, the increment of urinary TBARs in UUO mice was entirely abolished by MnTBAP therapy, indicating an amelioration of oxidative stress. Meantime, we found that three types of SOD were all reduced in obstructed kidneys determined by qRT-PCR, which was unaffected by MnTBAP. Collectively, these results demonstrated an important role of mitochondrial oxidative stress in mediating the downregulation of sodium transporters in obstructive kidney disease.
输尿管梗阻与肾钠转运体表达降低有关，这会导致尿液浓缩能力受损。在本研究中，我们使用合成的线粒体超氧化物歧化酶2（SOD2）模拟物MnTBAP来研究线粒体氧化应激在调节梗阻性肾病中钠转运体的作用。单侧输尿管梗阻（UUO）7天后，通过qRT-PCR、蛋白质免疫印迹或免疫组织化学检测发现，包括NHE3、NCC、NKCC2和ENaCα在内的钠转运体整体减少。在这些钠转运体中，MnTBAP处理可部分逆转NHE3、NCC和NKCC2的下调。相比之下，ENaCα的减少不受MnTBAP影响。输尿管梗阻或MnTBAP治疗对ENaC的β和γ亚基没有显著影响。为了进一步证实MnTBAP的抗氧化作用，我们检测了从UUO小鼠梗阻输尿管和假手术小鼠膀胱收集的尿液中的TBARs水平。正如预期的那样，MnTBAP治疗完全消除了UUO小鼠尿液中TBARs的增加，表明氧化应激得到改善。同时，我们通过qRT-PCR发现梗阻肾脏中三种类型的SOD均减少，且不受MnTBAP影响。总体而言，这些结果表明线粒体氧化应激在介导梗阻性肾病中钠转运体下调方面具有重要作用。
